Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intracellular cyclic nucleotide levels play an important role in the regulation of several immunological processes. Since elevation of intracellular cyclic adenosine monophosphate and/or cyclic guanosine monophosphate concentration by inhibition of phosphodiesterase (PDE) is known to modulate the inflammatory response, we compared the effect of amrinone, an inhibitor of the PDE III isoenzyme, and of theophylline, a nonspecific PDE inhibitor, on the plasma tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-10 (IL-10), and nitric oxide response in mice to intraperitoneal injection of bacterial lipopolysaccharide (LPS). Intraperitoneal treatment of animals with amrinone (100 mg/kg) 30 min before LPS administration decreased both plasma IL-6 and IL-10 concentrations in the first phase of the response, but enhanced plasma levels of these cytokines in the second part. In contrast, pretreatment of the animals with theophylline (100 mg/kg) enhanced LPS-induced plasma IL-6 and IL-10 levels during the whole response. However, pretreatment with both PDE inhibitors resulted in a marked inhibition of LPS-evoked plasma concentrations of TNF-alpha and nitrite/nitrate (breakdown products of nitric oxide) throughout the response. This study demonstrates for the first time that amrinone and theophylline possess differential, but primarily anti-inflammatory, properties during LPS-induced systemic inflammation in the mouse.
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PMID:Amrinone and theophylline differentially regulate cytokine and nitric oxide production in endotoxemic mice. 916 73

Effects of zaprinast, an inhibitor of guanosine 3', 5'-cyclic monophosphate (cGMP)-specific phosphodiesterase, and methylene blue, an inhibitor of soluble guanylate cyclase, on the negative chronotropic response to CD-832, a novel dihydropyridine derivative with a nitrate moiety, and nifedipine were examined with isolated guinea-pig right atria in the presence and absence of isoproterenol. CD-832 and nifedipine produced concentration-dependent negative chronotropic effects both in the absence and presence of isoproterenol. In the absence of isoproterenol, the concentration-response curves for CD-832 and nifedipine were neither potentiated by zaprinast nor inhibited by methylene blue. In the presence of isoproterenol (10[-8] M), zaprinast produced a three-fold leftward shift of the concentration-response curve for CD-832, while methylene blue produced a three-fold rightward shift. The concentration-response curve for nifedipine was not affected by these agents. SIN-1, a nitric oxide (NO) donor, had no chronotropic effect in the absence of isoproterenol, but had a concentration-dependent negative chronotropic effect in the presence of isoproterenol: the beating rate decreased to values close to that in the absence of isoproterenol. These findings suggest that NO-cGMP mediated pathway is involved in the negative chronotropic actions of CD-832 under beta-adrenergic stimulation.
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PMID:Possible involvement of nitric oxide-cGMP pathway in the negative chronotropic effect of CD-832, a novel dihydropyridine derivative. 949 12

Soluble guanylyl cyclase (sGC), an enzyme involved in cGMP signal transduction, is activated by NO binding to the endogenous heme. The mechanism of deactivation is not known. In tissues, cGMP levels decrease within minutes, despite the fact that sGC is activated to levels above the phosphodiesterase activity. Simple dissociation of NO from the heme in sGC has been suggested as a possible deactivation mechanism; however, dissociation rates of NO from ferrous heme proteins are typically very slow. Since oxidants and reductants are known to affect sGC activity, we have tested the effect of a variety of redox-active agents on the activity of NO-activated sGC. All the redox-active compounds tested, covering a wide range of reduction potentials, selectively deactivated the NO-activated sGC while having little or no effect on the basal activity of the enzyme. Among the reagents studied in detail, deactivation of sGC by air occurred slowly, while deactivation by ferricyanide was faster and methylene blue was fastest. The mechanism of deactivation of sGC by dioxygen in the air is straightforward: the heme is oxidized to Fe(III)heme and nitrate is formed. This reaction is similar to that of dioxygen with NOHb and NOMb as occurs in cured meats. Methylene blue and ferricyanide deactivate sGC by a different, as yet undetermined, mechanism.
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PMID:The deactivation of soluble guanylyl cyclase by redox-active agents. 950 Aug 37

Tetramethylpyrazine, an inhibitor of phosphodiesterase, has been widely used for treatment of cardiovascular diseases in China. Here, we investigate the effects of tetramethylpyrazine on hypotension, vascular hyporeactivity to norepinephrine (NE), release of tumor necrosis factor-alpha (TNF alpha) and nitric oxide (NO) in a rat model of circulatory shock induced by bacterial endotoxin (E. coli lipopolysaccharide, LPS). Male Wistar-Kyoto rats were anesthetized and instrumented for the measurement of mean arterial pressure (MAP) and heart rate (HR). Injection of LPS (10 mg/kg, i.v.) resulted in a fall in MAP and an increase of HR. In contrast, animals pretreated with tetramethylpyrazine (10 micrograms/kg, i.p. at 30 min prior to LPS) maintained a significantly higher MAP, but tachycardia was further enhanced at 60 min and 120 min when compared to rats given only LPS (LPS-rats). The pressor effect of NE (1 microgram/kg, i.v.) was also significantly reduced after treatment of rats with LPS. Similarly, the thoracic aorta obtained from rats after in vivo studies showed a significant reduction in the contractile responses elicited by NE (1 microM). Pretreatment of LPS-rats with tetramethylpyrazine partially, but significantly, prevented this LPS-induced hyporeactivity to NE in vivo and ex vivo. The injection of LPS resulted in a significant increase in the plasma TNF alpha level at 60 min, whereas the effect of LPS on the plasma nitrate (an indicator of NO formation) level increased in a time-dependent manner. This increment of both TNF alpha and nitrate levels induced by LPS was significantly reduced in LPS-rats pretreated with tetramethylpyrazine. The early hypotension caused by LPS was slightly, but significantly, prevented by pretreatment with tetramethylpyrazine, suggesting that tetramethylpyrazine affects the endothelial constitutive NOS (eNOS). This was examined by the effect of tetramethylpyrazine on acetylcholine (ACh, 1 microM)-induced relaxation in rats treated with tetramethylpyrazine for 4 h. However, tetramethylpyrazine had no significant effects on the ACh-induced relaxation, indicating that tetramethylpyrazine does not affect the activity of eNOS. Thus, tetramethylpyrazine attenuates the early hypotension and the delayed circulatory failure caused by endotoxin in the rat. These effects may be due to inhibition of the release of circulation factors and TNF alpha, which usually reveal synergism upon the induction of iNOS.
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PMID:Beneficial effects of tetramethylpyrazine, an active constituent of Chinese herbs, on rats with endotoxemia. 953 20

We evaluated the effects of oral administration of E4021 (100 mg/kg/day), a type V phosphodiesterase inhibitor, on immunoreactivities of endothelin-1, endothelin receptors, and nitric oxide synthases in pulmonary arteries in a rat model of pulmonary hypertension. Immunoreactivities of endothelin-1 and endothelial nitric oxide synthase were observed significantly less frequently, together with significant reduction of right ventricular overload and medial thickening in rats treated with E4021 than in the control with monocrotaline on day 28. The levels of plasma endothelin-1 and serum nitrite and nitrate were significantly lower in rats that received E4021 than in the control with monocrotaline. Oral administration of E4021 modulates endogenous immunoreactivities of endothelin-1 and endothelial nitric oxide synthase with the improvement or right ventricular overload and medial thickening.
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PMID:Type V phosphodiesterase inhibition modulates endogenous immunoreactivities of endothelin-1 and endothelial nitric oxide synthase in pulmonary arteries in rats with monocrotaline-induced pulmonary hypertension. 963 94

Sildenafil citrate, an oral therapy for erectile dysfunction, is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), the predominant isozyme metabolizing cGMP in the corpus cavernosum. Chemically, it is a compound of the pyrazolo-pyrimidinyl-methylpiperazine class. Sildenafil has no direct relaxant effect on human corpus cavernosum but enhances the relaxant effect of nitric oxide (NO) on the corpus cavernosum by inhibiting PDE5, which is responsible for degradation of cGMP in this tissue. When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil increases concentrations of cGMP in the corpus cavernosum, causing smooth muscle relaxation and blood flow into the penis, resulting in an erection. Sildenafil at recommended doses has no effect in the absence of sexual stimulation. The drug is rapidly absorbed after oral administration, with absolute bioavailability of 40%. Its pharmacokinetics are dose proportional over the recommended dosage range. Maximum plasma concentrations are reached within 30 to 120 minutes after oral dosing in the fasting state. Sildenafil is cleared predominantly by the hepatic microsomal isoenzymes CYP3A4 (major route) and CYP2C9 (minor route). Clinical studies assessed the effect of sildenafil on the ability of men with erectile dysfunction to engage in sexual activity and, specifically, to achieve and maintain an erection sufficient for satisfactory sexual intercourse. Sildenafil was evaluated at doses of 25, 50, and 100 mg in randomized, double-masked, placebo-controlled clinical trials of up to 6 months' duration. The drug was administered to hundreds of patients aged 19 to 87 years having erectile dysfunction of various etiologies for a mean duration of 5 years. Sildenafil was associated with statistically significant improvement in erectile function compared with placebo. Adverse effects reported at a rate of >2% were headache, flushing, dyspepsia, nasal congestion, urinary tract infection, abnormal vision, diarrhea, dizziness, and rash. No cases of priapism were reported. The use of sildenafil is contraindicated in men who are taking organic nitrates, because of the potential for a precipitous decrease in blood pressure. Postmarketing reports and surveillance have revealed at least 39 deaths with sildenafil use in men having a history of heart disease, men taking nitrate medications, and men in poor physical health due to lack of exercise. Many of the men who experienced serious adverse effects or death had a variety of concomitant diseases and were taking multiple medications.
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PMID:Safety and efficacy of sildenafil citrate in the treatment of male erectile dysfunction. 991 1

Sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), is a well-tolerated and highly effective treatment for erectile dysfunction. The mechanism of action of sildenafil depends on activation of the nitric oxide (NO)-cGMP pathway during sexual stimulation, which results in corpus cavernosal smooth muscle relaxation and penile erection. Endogenously derived NO is also involved in blood pressure regulation through its effect on basal vascular tone, which is mediated by cGMP levels. Organic nitrates and NO donors exert their therapeutic effects on blood pressure and vascular smooth muscle by the same mechanism as endogenous NO. Since both sildenafil and organic nitrates exert their pharmacologic effects via increases in cGMP concentrations, a double-blind, placebo-controlled, crossover study was undertaken to investigate the effects of sildenafil coadministered with glyceryl trinitrate on blood pressure and heart rate in healthy male subjects. The hemodynamic effects of sildenafil were also evaluated in a second placebo-controlled crossover study in men with hypertension who were taking the calcium antagonist amlodipine, which has a mechanism of action that does not involve the cGMP pathway. In the first crossover study, subjects were treated with oral sildenafil (25 mg, 3 times a day for 4 days) or placebo and then challenged on day 4 with a 40-minute, stepwise, intravenous infusion of glyceryl trinitrate (0.5 mg/mL in 5% dextrose at an initial infusion rate of 2.5 microg/min and doubling every 5 minutes to a maximum rate of 40 microg/min) 1 hour after taking sildenafil or placebo. On day 5, subjects received a sublingual glyceryl trinitrate tablet (500 microg) 1 hour after taking 25 mg of sildenafil or placebo. During sildenafil treatment, the subjects were significantly less tolerant of intravenously administered glyceryl trinitrate than during placebo treatment, based on the occurrence of a >25 mm Hg decrease in blood pressure or the incidence of symptomatic hypotension (p <0.01). When a sublingual glyceryl trinitrate tablet was administered on day 5, a 4-fold greater decrease in systolic blood pressure was observed for the subjects during the sildenafil treatment period than during the placebo treatment period. The changes in heart rate were negligible during both glyceryl trinitrate challenges. In conclusion, sildenafil potentiated the hypotensive effects of glyceryl trinitrate, an organic nitrate. Thus, sildenafil administration to patients who are using organic nitrates, either regularly and/or intermittently, in any form is contraindicated. In the second crossover study, men with hypertension, who were taking 5 or 10 mg/day of amlodipine, received a single oral dose of 100 mg sildenafil or placebo. Coadministration of sildenafil did not significantly affect the pharmacokinetics of amlodipine. In the 4 hours after dosing, differences in the mean maximum change from baseline in supine systolic and diastolic blood pressures between the sildenafil plus amlodipine and the placebo plus amlodipine treatment periods were -8 mm Hg and -7 mm Hg, respectively (p < or =0.002). The mean maximum supine heart rate increased 2.1 beats/min during sildenafil plus amlodipine treatment and decreased 1.5 beats/min during placebo plus amlodipine treatment (p <0.02). The adverse events in this study were predominantly mild or moderate and did not cause discontinuation of treatment. Adverse events considered to be related to sildenafil treatment included headache, nausea, and dyspepsia. In patients with hypertension who were taking amlodipine therapy, sildenafil produced additive, but not synergistic, reductions in blood pressure. The difference in the mean maximum change from baseline in blood pressure between sildenafil plus amlodipine and placebo plus amlodipine was comparable to the decrease in blood pressure reported for healthy men taking sildenafil alone. (ABSTRACT TRUNCATED)
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PMID:Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist. 1007 39

Erectile dysfunction is a common condition in men with cardiovascular disease, probably as a result of shared factors that impair hemodynamic mechanisms in the penile and ischemic vasculature. Sildenafil citrate, an orally active, selective inhibitor of phosphodiesterase type 5 (PDE5), has demonstrated excellent efficacy and safety profiles in men with erectile dysfunction of various etiologies. Sildenafil administration is contraindicated in patients who are taking nitrates or nitric oxide donors. This retrospective subanalysis of data from double-blind, placebo-controlled studies assessed the efficacy (9 studies) and safety (11 studies) of sildenafil in patients with erectile dysfunction and ischemic heart disease who were not taking nitrates. Of 3,672 patients randomized to receive sildenafil (5-200 mg) or placebo for 4-24 weeks in 11 double-blind, placebo-controlled studies, 357 (10%) reported a history (past or present) of ischemic heart disease and were not taking nitrates. Efficacy was assessed using end-of-treatment responses to Question 3 (ability to achieve an erection) and Question 4 (ability to maintain an erection) of the International Index of Erectile Function (IIEF), scores for the 5 domains of male sexual function assessed by the IIEF (erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction), and responses to a global efficacy question ("Did the treatment improve your erections?"). The responses to the 2 IIEF questions were graded on a scale of 1 (almost never or never) to 5 (almost always or always), with a score of 0 indicating no attempt at sexual intercourse. At the end of treatment, the mean scores for Question 3 and Question 4 of the IIEF for patients with erectile dysfunction and ischemic heart disease were significantly higher for the sildenafil group than for the placebo group (p <0.0001). Mean end-of-treatment scores for the IIEF domains also demonstrated significant increases for sildenafil-treated patients compared with those receiving placebo (p <0.05). At the end of treatment, improved erections were reported by 70% of patients who received sildenafil and by 20% of those in the placebo group p <0.0001). For the sildenafil group, the incidences of the most common adverse events (headache 25%, flushing 14%, and dyspepsia 12%) for patients with ischemic heart disease were similar to those in patients without this concomitant illness (21%, 15%, and 10%, respectively). Moreover, the overall incidence of cardiovascular adverse events other than flushing was comparable in patients with and without ischemic heart disease for both treatment groups. Since there is a degree of cardiac risk associated with sexual activity, clinicians should consider the patient's cardiovascular status before initiating any treatment for erectile dysfunction. Physicians should be aware that patients with underlying cardiovascular disease could be adversely affected by the vasodilator effects of sildenafil, especially in combination with sexual activity. The results of the present subanalysis indicate that oral sildenafil significantly improves erectile function and is well tolerated in patients with erectile dysfunction and ischemic heart disease who are not taking nitrate therapy.
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PMID:Efficacy and safety of sildenafil citrate in the treatment of erectile dysfunction in patients with ischemic heart disease. 1007 40

Nitric oxide (NO) is a well-documented effector molecule in rodent phagocytes but its synthesis in human neutrophils has been controversial. In this study, NO production in human neutrophils activated by chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (fMLP) was measured in the presence of L-arginine (L-Arg) and N(G)-hydroxy-L-arginine (OH-L-Arg), the precursor and intermediate amino acids in NO synthesis, respectively. Incubation of fMLP-activated neutrophils with OH-L-Arg resulted in a production of nitrite, nitrate, and citrulline that was greater than with unstimulated neutrophils but was not inhibited by the NOS inhibitors L-NMMA and L-NIO or the cytochrome P450 inhibitor troleandomycin and was not seen when OH-L-Arg was replaced with L-Arg. This nitrite, nitrate, and citrulline production was not associated with any detectable NO synthesis because no increases in cyclic GMP were observed in the presence of phosphodiesterase inhibitors and in the presence or absence of superoxide dismutase. Moreover, no increases in the formation of the reaction product of NO with superoxide, peroxynitrite, were observed on addition of either OH-L-Arg or L-Arg to activated neutrophils, as assessed either by dihydrorhodamine oxidation or protein nitration. This suggests that, in spite of the production of nitrite, nitrate, and citrulline, commonly used indicators of NO formation, normal human blood neutrophils, are not producing detectable amounts of either NO or peroxynitrite when stimulated with fMLP in the presence of OH-L-Arg.
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PMID:No detectable NO synthesis from L-arginine or N(G)-hydroxy-L-arginine in fMLP-stimulated human blood neutrophils despite production of nitrite, nitrate, and citrulline from N(G)-hydroxy-L-arginine. 1041 Oct

Sildenafil citrate (Viagra) is a new oral medication that inhibits phosphodiesterase-5 (PDE5) in the corpus cavernosum to facilitate penile erection for the treatment of male impotence. The drug also has a mild inhibitory effect on PDE6, which controls the level of cyclic guanosine monophosphate in the retina, and it may cause a perception of bluish haze or increased light sensitivity in some patients. Long-term retinal damage has not been reported, but long-term electroretinographic studies have not been performed. Sildenafil causes a mild lowering of blood pressure and is absolutely contraindicated in patients taking any form of nitrate medication. A number of cardiovascular deaths and retinal vascular events in patients taking sildenafil have been reported, but so far the rate of these complications does not exceed expectation for an elderly population. Ophthalmologists should alert patients to the ocular side effects and potential risks of this new drug until further clinical experience has been obtained.
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PMID:Sildenafil (Viagra) and ophthalmology. 1054 Nov 53


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